Abstract
MacroD1 is a macrodomain containing protein that has mono-ADP-ribose hydrolase enzymatic activity toward several ADP-ribose adducts. Dysregulation of MacroD1 expression has been shown to be associated with the pathogenesis of several forms of cancer. To date, the physiological functions and sub-cellular localization of MacroD1 are unclear. Previous studies have described nuclear and cytosolic functions of MacroD1. However, in this study we show that endogenous MacroD1 protein is highly enriched within mitochondria. We also show that MacroD1 is highly expressed in human and mouse skeletal muscle. Furthermore, we show that MacroD1 can efficiently remove ADP-ribose from 5′ and 3′-phosphorylated double stranded DNA adducts in vitro. Overall, we have shown that MacroD1 is a mitochondrial protein with promiscuous enzymatic activity that can target the ester bonds of ADP-ribosylated phosphorylated double-stranded DNA ends. These findings have exciting implications for MacroD1 and ADP-ribosylation within the regulation of mitochondrial function and DNA-damage in vivo.
Highlights
ADP-ribosylation is a chemical modification and is involved in the regulation of a number of processes including stress response, transcription, chromatin structure, DNA damage repair, cell division and apoptosis (Gibson and Kraus, 2012; Barkauskaite et al, 2015; Gupte et al, 2017; Palazzo et al, 2017)
Mammalian poly(ADP-ribose) polymerases (PARPs) have been most extensively studied within the context of DNA repair, they have been implicated in chromatin remodeling, transcription, unfolded-protein response, cellular stress response, host–virus interactions and many more (Gupte et al, 2017)
We show that MacroD1 is primarily a mitochondrial protein, located within the mitochondrial matrix (MM) and that the N-terminal region of MacroD1 protein is required for mitochondrial localization
Summary
ADP-ribosylation is a chemical modification and is involved in the regulation of a number of processes including stress response, transcription, chromatin structure, DNA damage repair, cell division and apoptosis (Gibson and Kraus, 2012; Barkauskaite et al, 2015; Gupte et al, 2017; Palazzo et al, 2017). Mammalian PARPs have been most extensively studied within the context of DNA repair, they have been implicated in chromatin remodeling, transcription, unfolded-protein response, cellular stress response, host–virus interactions and many more (Gupte et al, 2017). Some members of the PARP superfamily, such as PARP1/2 and Tankyrases (PARP5a and PARP5b), can make PAR chains while most other PARP family members have MART activity (D’Amours et al, 1999; Feijs et al, 2013; Vyas et al, 2014; Pascal and Ellenberger, 2015)
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